| First Author | Gencer S | Year | 2017 |
| Journal | Sci Signal | Volume | 10 |
| Issue | 502 | PubMed ID | 29066540 |
| Mgi Jnum | J:259042 | Mgi Id | MGI:6140564 |
| Doi | 10.1126/scisignal.aam7464 | Citation | Gencer S, et al. (2017) TGF-beta receptor I/II trafficking and signaling at primary cilia are inhibited by ceramide to attenuate cell migration and tumor metastasis. Sci Signal 10(502) |
| abstractText | Signaling by the transforming growth factor-beta (TGF-beta) receptors I and II (TbetaRI/II) and the primary cilia-localized sonic hedgehog (Shh) pathway promote cell migration and, consequently, tumor metastasis. In contrast, the sphingolipid ceramide inhibits cell proliferation and tumor metastasis. We investigated whether ceramide metabolism inhibited TbetaRI/II trafficking to primary cilia to attenuate cross-talk between TbetaRI/II and the Shh pathway. We found that ceramide synthase 4 (CerS4)-generated ceramide stabilized the association between TbetaRI and the inhibitory factor Smad7, which limited the trafficking of TbetaRI/II to primary cilia. Expression of a mutant TbetaRI that signals but does not interact with Smad7 prevented the CerS4-mediated inhibition of migration in various cancer cells. Genetic deletion or knockdown of CerS4 prevented the formation of the Smad7-TbetaRI inhibitory complex and increased the association between TbetaRI and the transporter Arl6 through a previously unknown cilia-targeting signal (Ala(31)Thr(32)Ala(33)Leu(34)Gln(35)) in TbetaRI. Mutating the cilia-targeting signal abolished the trafficking of TbetaRI to the primary cilia. Localization of TbetaRI to primary cilia activated a key mediator of Shh signaling, Smoothened (Smo), which stimulated cellular migration and invasion. TbetaRI-Smo cross-talk at the cilia in CerS4-deficient 4T1 mammary cancer cells induced liver metastasis from orthotopic allografts in both wild-type and CerS4-deficient mice, which was prevented by overexpression of Smad7 or knockdown of intraflagellar transport protein 88 (IFT88). Overall, these data reveal a ceramide-dependent mechanism that suppresses cell migration and invasion by restricting TbetaRI/II-Shh signaling selectively at the plasma membrane of the primary cilium. |
